Title:ClpP Peptidase as a Plausible Target for the Discovery of Novel
Antibiotics
Volume: 25
Issue: 2
关键词:
AMR，抗生素，ClpP，毒力，传染病，抗菌素耐药性。
摘要: Antimicrobial resistance (AMR) to currently available antibiotics/drugs is a global
threat. It is desirable to develop new drugs that work through a novel target(s) to avoid drug resistance.
This review discusses the potential of the caseinolytic protease P (ClpP) peptidase complex
as a novel target for finding novel antibiotics, emphasising the ClpP’s structure and function. ClpP
contributes to the survival of bacteria via its ability to destroy misfolded or aggregated proteins. In
consequence, its inhibition may lead to microbial death. Drugs inhibiting ClpP activity are currently
being tested, but no drug against this target has been approved yet. It was demonstrated that Nblocked
dipeptides are essential for activating ClpP’s proteolytic activity. Hence, compounds mimicking
these dipeptides could act as inhibitors of the formation of an active ClpP complex. Drugs,
including Bortezomib, Cisplatin, Cefmetazole, and Ixazomib, inhibit ClpP activation. However,
they were not approved as drugs against the target because of their high toxicity, likely due to the
presence of strong electrophiles in their warheads. The modifications of these warheads could be a
good strategy to reduce the toxicity of these molecules. For instance, a boronate warhead was replaced
by a chloromethyl ketone, and this new molecule was shown to exhibit selectivity for
prokaryotic ClpP. A better understanding of the structure and function of the ClpP complex would
benefit the search for compounds mimicking N-blocked dipeptides that would inhibit ClpP complex
activity and cause bacterial death.
